Hypothesis Watch

Just for fun, I thought I'd list all the hypotheses about ME/CFS that I can remember. Hopefully others will add ones I've missed, but preferably without detailed justification of your favourite models, just the main idea - and link to more resources as appropriate.

It's possible (probable?) that the eventaul cause(s) of CFS will be in these hypotheses, though they can't all be Elvis.

The only broad categorisation I'd make is between those that suggest a chronic, ongoing cause of CFS eg XMRV and those that suppose a trigger (or triggers) that can lead to an ongoing state of CFS even when the original trigger is no longer present. Maybe other people can suggest better ways to group them.

TRIGGER plus

The Biopsychosocial model
Flawed patient beliefs and behaviours perpetuate the 'illness'. The clear winner in terms of research spend, employment and publications

An old one many don't know is the idea of molybdenum deficiency. It is needed for detox enzymes in the mitochondria, hence a deficiency will induce mitochondiral dysfunction.

Aquired mitochondrial dysfunction is also taking off as a model. It ties in nicely with oxidative and nitrosative stress models including the methylation cycle model (which is in turn can be viewed as another deficiency model, not just epigenetic or due to polymorphisms).

An older one I was aware of is the model that it is due to a dysregulation of eicosanoid synthesis, hormones that regulate every cell in the body. This was proposed by Martinovic.

On the genetic front at least two different mutations in Cortisol Binding Globulin induce symptoms that resemble CFS or ME.

On toxins, mold really has to be there.

Rituximab implies B cell mediation in symptoms - but there are alternative theories for this including auto-antibodies, cytokines and carrying pathogens. So it fits with several different categories. It would be ironic if it turned out it was all three - cytokines plus antibodies plus pathogens.

Another theory that is often not mentioned is parasitic infection - some parasites have immune modifying chemicals that knock out the defence systems.

Its also possible that several of the theories are correct, but for different subgroups.

I will think of more. My brain is just fried for the day - maybe tomorrow if I recall to come back here.

Rituximab implies B cell mediation in symptoms - but there are alternative theories for this including auto-antibodies, cytokines and carrying pathogens. So it fits with several different categories. It would be ironic if it turned out it was all three - cytokines plus antibodies plus pathogens.

Its also possible that several of the theories are correct, but for different subgroups.

Could you explain mold? Is that mold producing toxins in the environment, or is it the mold itself causing the problem in the body?

Also, could you explain a bit more about this:

Aquired mitochondrial dysfunction is also taking off as a model. It ties in nicely with oxidative and nitrosative stress models including the methylation cycle model (which is in turn can be viewed as another deficiency model, not just epigenetic or due to polymorphisms).

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I agree different of these ideas may account for different sub-groups, but I'd bet my proverbial house that most of them are wrong (that's science for you). Equally I'd bet that at least one significant cause of CFS is not on this list either; probably one reason CFS hasn't been solved yet is no one has asked the right question. Certainly that seems to be the pattern in other fields before there's a breakthrough: lots of tantalising clues but nothing really conclusive, or agreed on, until someone comes up with the theory/experiment that makes sense of (almost) everything. Though as Francis Crick said, "a theory that fits all the facts will be wrong, because some of the 'facts' will be wrong".

I am about to crash for a few hours in the hope that I might wake up more functional, but I will give your questions a go, and maybe come back later again when I am less zonked.

Mold is an old theory, its thought to be mold toxins I think, and an association with mold was with the Lake Tahoe outbreak from what I gather. Its not my area of expertise, but its a credible model for a subset of patients.

There is a book on acquired mitochondrial disorders that was just released, there is a thread on it here. One the things that has been happening in the last few years is that pathophysiological models are merging due to substantial overlap. The nitrosative stress models (eg. Pall's Tenth Paradigm) lead to oxidative stress, and they tie into methylation for several reason including BH4. Rich could probably expand on this better than me, or maybe I will say more when my brain restarts.

Lately I have been looking at folate issues more as deficiency than genetics. If you have a genetic problem your risk of developing methylation problems increases, but even if you don't you are still at risk. One of the things driving it is the discovery that four out of five post menopausal women have excessive folic acid - they cannot metabolize it. If they have this problem, how many others do too? To metabolize it requires a number of steps and factors, and deficiencies in several are suspected. Genetic bias is only part of the risk. Addition of folic acid to cereal, bread, etc, which in some countries is mandated by regulation, plus its use in supplements, can drive this excess folic acid and this will compete with other forms of folate with various enzymes in the body. So the net effect is high blood folic acid but low methyl folate, leading to methyl folate deficiency effects. This in turn ties into the other methylation issues including glutathione depletion.

Any disease or injury that depletes NADPH might also induce these problems, and this could include either viral infection or the immune reaction to viral infection.

The pieces are starting to fit together, and this needs a really broad review but I don't have time (too many other projects). I am definitely interested in getting the acquired mitochondrial dysfunction book though.

Great idea .. But, isn't this a list of possible causes rather than hypothesis ? I heard that getting me/cfs could mean the patient has one or more of the problems you listed.

I also wanted to add celiac disease and gluten sensitivity to your list. The nih recognized back in 2006, at least, that celiac is being misdiagnosed as cfs. They're not up on gluten sensitivity that I know of but hopefully they will be soon.

just did big edit on my post. I some how missed seeing something already in your list.

Where you have deficiencies. Someone may be having a good intake of something but it could be due to a metabolic issue, in which one has conversion issues of the nutrient... which may even be a nutrient they havent discovered yet.

I also wonder if we could have some kind of undiscovered tick borne illness (ticks. whether fleas or whatever or everywhere). Like lyme but not lyme.

It makes no sense that govenments put so little funding into ME/CFS when there are so many different things to be looking at. Our illness could lead to some huge new discovery.

I think care must be taken not to overstate that Francis Crick quote ("a theory that fits all the facts will be wrong, because some of the 'facts' will be wrong"). Certainly, requiring theorized causes to explain incorrect "facts" could preclude correct theories from consideration. At the same time, however, if a theorized cause cannot explain the preponderance of well-supported observations, it should be considered highly speculative if not "dead on arrival." A theorized cause must at least be able to plausibly explain most of what it purports to cause. Otherwise, it is indistinguishable from mysticism: theory + magic = disease.

To that end, I would call everything under the "trigger plus" category dead on arrival, esp. the biopsychosocial model. These all blithely overlook one of the most indisputable "facts" pertaining to ME/CFS: its chronicity. I have yet to hear from the biopsychosocial school even an attempt to provide a plausible mechanism for chronic disease perpetuation following their almighty trigger. The commonplace nature of their purported triggers (childhood stress, etc) plus zero attempt to explain how the disease actually perpetuates, renders their theories meaningless. One might as well theorize that ME/CFS is triggered by wearing shoes, which sometimes mysteriously initiates "long-term changes" that mysteriously enable ongoing disease, even in the absence of future shoe-wearing.

Furthermore, using the trigger to classify the disease is backwards. The ongoing disease process (the "magic" part of the biopsychosocial equation) is the disease, regardless of the trigger. No doubt the biopsychosocialists would try to classify an amputee as a narcoleptic if his amputation was precipitated by his/her falling asleep at the wheel.

I would like to suggest a distinction between hypotheses that deal with the etiology or etiologies (root cause or causes) of ME/CFS, and those that deal with the pathogenesis (development of the disease process) and pathophysiology (changes in the normal function of the body that are caused by the disease).

My current view is that there are many root causes or etiologies, and they differ from case to case of ME/CFS. I base this on my own interactions with many PWMEs over the past 16 years as well as the published so-called "risk factor" studies that examine the factors reported by PWMEs in their case histories.

But in order for this disorder to have a singular identity and be defined as a single disorder, the various PWMEs must have the essence of their pathophysiology in common, because ME/CFS is defined in terms of its symptoms, and the symptoms must arise out of the pathophysiology.

A common pathophysiology implies at least the same endpoint of the pathogenesis for all PWMEs, though the beginning of the pathogenesis may differ somewhat from case to case, because the pathogenesis must be able to link differing etiologies with a common pathophysiology, in order to produce symptoms in common.

I hope that makes sense.

The GD-MCB hypothesis meets these criteria. The various differing root causes are brought together by their common effect on the depletion of glutathione, which is intimately tied to one of the best-documented biochemical abnormalities of ME/CFS, i.e. oxidative stress. Glutathione depletion has been verified by lab testing, as have several markers for oxidative stress.

The pathogenesis and pathophysiology then flow naturally from this. New research published last year explains why glutathione depletion interferes with B12 metabolism so strongly, producing a functional B12 deficiency, and in many cases that can be confirmed by elevated methylmalonate in the urine.

Functional B12 deficiency leads directly to inhibition of the activity of methionine synthase, which takes down the methylation cycle, and that can be verified with the methylation pathways panel.

The methyl trap mechanism and catabolism of methylfolate by elevated peroxynitrite due to the oxidative stress then cause loss of the folates, and this too is verified with the methylation pathways panel.

Methionine drops because of draining of homocysteine into the transsulfuration pathway, followed by sulfoxidation and excretion of sulfate. These, too, are verified by lab tests.

The symptoms of ME/CFS can all be predicted from the vicious circle mechanism produced by the above steps. This is elaborated in the video and slides here:

This has become a pretty tight cause and effect sequence with recent developments, and each step is now verified by testing. The sequence is self-consistent in terms of known biochemistry and physiology.

In my view, the challenges that remain are in identifying and treating the etiologies in each case. This is still difficult, partly because we may not yet know all the possible etiologies, and some of the ones that have been identified, such as Lyme disease, mold illness, and entrenched viral infections, are not easily diagnosed or treated at present.

I do think that that pathogeneses and pathophysiology are pretty well in hand now, and treating the pathophysiology with methylation protocols does help most PWMEs. In cases where it does not, the issues seem to be deficiencies of supporting cofactor nutrients, major gut dysbiosis, or high body burdens of toxins. We do have means of detecting these and treating them, but it requires individual testing and treatment, depending on the particular issues involved in each case.

The methylation pathways panel is growing in usage as more physicians are starting to order it. About 40 or 50 of these analyses are being run each week now. This panel is being used more in the autism and Lyme communities now as well. Methylation treatment is becoming part of the overall protocol for treating chronic Lyme disease among the LLMD docs.

I think the main thing holding back even more growth of this testing and treatment in the mainstream medical community is the lack of a rigorous clinical trial of methylation-type treatment in ME/CFS, but this is not holding back the integrative physicians. Publication of our paper in the Townsend Letter in December, 2011 has gotten information about this panel and treatment out to more of the integrative and alternative medical communities. The Swedish seminar video has been watched by over 700 people worldwide, and this is spreading word of this testing and treatment internationally.

We still have a lot of work to do, but I am encouraged by these developments, and I very much appreciate the help that the Phoenix Rising community has been giving me in this research.

"I would like to suggest a distinction between hypotheses that deal with the etiology or etiologies (root cause or causes) of ME/CFS, and those that deal with the pathogenesis (development of the disease process) and pathophysiology (changes in the normal function of the body that are caused by the disease)." post 8

I have also been tihinking about Rituximab more. I think there is an alternative view that might have been missed though I am not sure, and I have not gone back to check the published research on this regarding cytokine shifts. This is a variation of the cytokine view of why Rituximab works. The Th1 versus Th2 bias in people is shifted heavily toward Th2. That means its B cell mediated, with cytokines and possibly other factors doing the regulation. Remove the Th2 bias by removing the B cells and the Th1 bias can reassert - but this takes time. Its not instant. If the Th2 bias reasserts as the B cells are stored, then the symptoms come back. If Th1 remains dominant after the B cells are restored, then the CCC CFS or ME is in full remission.

This model has several important points. First, if its correct then its easily tested. What is the cytokine balance before and after treatment with Rituximab. What is the cytokine balance of those in full remission. Of those who do not need repeat treatments? Of those who do need repeat treatments, both before and after the repeat treatment?

A second testable issue is that addition of agents to promote a Th1 bias during the B cell restoration will susbstantially enhance the chance of full remission.

But in order for this disorder to have a singular identity and be defined as a single disorder, the various PWMEs must have the essence of their pathophysiology in common, because ME/CFS is defined in terms of its symptoms, and the symptoms must arise out of the pathophysiology.

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The same clinical symptoms do not have to arise from the same pathophysiology. In fact many times similar symptoms can arise from very different pathophysiological processes.

For example shortness of breath can be the result of heart failure, Chronic obstructive pulmonary disease,interstitial lung disease or neuromuscular disease. Each with a very different pathophisiology.
Chest pain can be the result of acute myocardial infarction, aortic dissection or peptic ulcer.
acute paralysis can be the result of stroke or MS.

Further more, the same pathphysiology may lead to very different clinical symptoms. Acute myocardial infarction can cause "classical" chest pain, but also jaw pain. MS can lead to sudden blindness, or loss of balance or paralysis. Celiac disease can cause weight loss, anemia, neurological symptoms, osteoporosis, or a "mix" of various symptoms. Leukemia can cause bleeding, anemia or "unexplained" neurological symptoms.

Diagnostic tests are also, many times, not specific for one disease. Because very different disease processes, can directly or indirectly effect similar biochemical pathways or physiological processes.

In some diseases the diagnosis is based on demonstration of the pathophysiological process (such as cancer), in others on the clinical symptoms alone (such as Parkinson's) and in others on some "mix" of both (such as SLE).

You can look at etiology, pathophysiology, clinical symptoms, diagnostic tests, diagnosis and treatment as multiple circles that cut each other, with areas of overlap.

There are very few diseases in which there is a unique clinical picture, unique pathophysiology, unique diagnostic tests and unique treatment.
I highly doubt that CFS will end up being such an illness. More likely it will be more like SLE, in which a group of symptoms combined with results of tests will define the diagnosis as-possible, probable and definite.
I also doubt that there will be one uniform treatment effective for all the patients.

A diagnosis in general is an imperfect tool that enables physicians to stratify patients, so that they could better make decisions regarding management and prognosis.

I take your point. However, I don't advocate focusing on a single symptom or a few symptoms. I favor use of a "systems" approach, as is used in engineering and the physical sciences. In ME/CFS there is a very large number of reported symptoms by various patients. I maintain that they can all be tracked back to a single pathophysiology, but this pathophysiology has to be worked out in detail, too. It's necessary to look at the whole picture, in my opinion, and when that is done, I maintain that it supports a single pathophysiological mechanism. Yes, there are variations, I think largely because of differing collections of genetic polymorphisms, and they are part of the complete picture that must be considered.

If you want to see what I mean about this kind of approach, I would suggest viewing the video or scanning the slides at this website:

"I would like to suggest a distinction between hypotheses that deal with the etiology or etiologies (root cause or causes) of ME/CFS, and those that deal with the pathogenesis (development of the disease process) and pathophysiology (changes in the normal function of the body that are caused by the disease)." post 8

I have also been tihinking about Rituximab more. I think there is an alternative view that might have been missed though I am not sure, and I have not gone back to check the published research on this regarding cytokine shifts. This is a variation of the cytokine view of why Rituximab works. The Th1 versus Th2 bias in people is shifted heavily toward Th2. That means its B cell mediated, with cytokines and possibly other factors doing the regulation. Remove the Th2 bias by removing the B cells and the Th1 bias can reassert - but this takes time. Its not instant. If the Th2 bias reasserts as the B cells are stored, then the symptoms come back. If Th1 remains dominant after the B cells are restored, then the CCC CFS or ME is in full remission.

This model has several important points. First, if its correct then its easily tested. What is the cytokine balance before and after treatment with Rituximab. What is the cytokine balance of those in full remission. Of those who do not need repeat treatments? Of those who do need repeat treatments, both before and after the repeat treatment?

A second testable issue is that addition of agents to promote a Th1 bias during the B cell restoration will susbstantially enhance the chance of full remission.

Bye, Alex

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Alex,

I think you haved provided some interesting questions/thoughts about Rituximab. I think the idea that this drug works as an autoimmune target is still an area of much debate and I would be interested to know your thoughts on how a Th1/Th2 dysfunction might rule in or out the autoimmune theories? I am assuming from reading your earlier posts that it may be autoimmune in some subsets, but not in others. Am I understanding this correctly? Any theories on what is the common trigger, which switches the viruses, pathogens etc... on in one group but not the others.

I think you may be right about this. I also think that Rituximab may lower the inflammation in connection with knocking out the B cells and altering the cytokine picture. This may give glutathione a chance to come up in some patients, before the B cells are restored. I still don't believe that ME/CFS is an autoimmune disorder, except for the Hashimoto's that can result from the glutathione depletion in the thyroid.

I think you may be right about this. I also think that Rituximab may lower the inflammation in connection with knocking out the B cells and altering the cytokine picture. This may give glutathione a chance to come up in some patients, before the B cells are restored. I still don't believe that ME/CFS is an autoimmune disorder, except for the Hashimoto's that can result from the glutathione depletion in the thyroid.

Best regards,

Rich

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Rich or others,

Have you explored the theory that EBV antigens are very similar to thyroid antigens and thus EBV (or perhaps other herpesviruses) may have some connection to the correlation between thyroid disorders and viral findings noted in some ME/CFS patients? Here are a few links discussing EBV and thyroid dysfunction, still looking for the reference that I had read earlier, which hypothesized that EBV antigens(?) might be trying to attach to thyroid receptors resulting in "clogged up" or "confused" receptor sites.

A Th2 shift is known to predispose toward antibodies, and hence autoimmunity. A Th2 shift and viral mimicry is not unknown. While I have heard of the EBV thyroid link, I have never taken the time to investigate it.

As for triggers, there have to be common biochemical pathways in my view, I have held that view since 1993. The question is which, of all the involved and relevant pathways, are the most critical? That is still an open question but being looked at by many including Rich.

I take your point. However, I don't advocate focusing on a single symptom or a few symptoms. I favor use of a "systems" approach, as is used in engineering and the physical sciences. In ME/CFS there is a very large number of reported symptoms by various patients. I maintain that they can all be tracked back to a single pathophysiology, but this pathophysiology has to be worked out in detail, too. It's necessary to look at the whole picture, in my opinion, and when that is done, I maintain that it supports a single pathophysiological mechanism. Yes, there are variations, I think largely because of differing collections of genetic polymorphisms, and they are part of the complete picture that must be considered.

If you want to see what I mean about this kind of approach, I would suggest viewing the video or scanning the slides at this website:

Well, really the best hypothesis is that it's caused by excessive brain wear listening to clueless, smug psychiatrists who couldn't diagnose the anal clap even though they've obviously had it a dozen times!